Primary endpoint: time to first disease progression event up to end of treatment

Triple Combination

OverallPopulation

TripleCombination

FC IITriple Combo

FC IIITriple Combo

Subgroup Analysis:GRIPHON—The ONLY PAH Outcomes Trial That Included PatientsTreated With TRIPLE-combination Therapy1-3*

Patients receiving ERA and PDE-5i at baseline were a prespecified subgroup for evaluation of the GRIPHON primary endpoint; however, the more detailed analyses described here are exploratory and post hoc. Sample size should be considered and results should be interpreted with caution.

Baseline patient characteristics and notable differences from overall population

33% (n=376) of all patients in GRIPHON were on ERA and PDE-5i background therapy at baseline†

The triple-combination subgroup had a longer time from diagnosis (3.8 years vs 2.4 years in the overall population), a larger percentage from Western Europe/Australia (52.9% vs 27.8%), and a larger percentage from North America (28.5% vs 16.7%)

This subgroup analysis was post hoc and exploratory. Sample size should be considered and results should be interpreted with caution.

Baseline patient characteristics and notable differences from overall population

10% (n=115) of all patients in GRIPHON were FC II on ERA and PDE-5i background therapy at baseline

The FC II triple-combination subpopulation had a longer time from diagnosis (4 years vs 2.4 years in the overall population), a larger percentage from Western Europe/Australia (43.5% vs 27.8%), and a larger percentage from North America (31.3% vs 16.7%)

This subgroup analysis was exploratory and post hoc. Sample size should be considered and results should be interpreted with caution.

Baseline patient characteristics and notable differences from overall population

22% (n=255) of all patients in GRIPHON were FC III on ERA and PDE-5i background therapy at baseline

The FC III triple-combination subpopulation had a longer time from diagnosis (3.8 years vs 2.4 years in the overall population), a larger percentage from Western Europe/Australia (56.9% vs 27.8%), a larger percentage from North America (27.5% vs 16.7%), and an older average age (52 years vs 48.1)

DRUG INTERACTIONS

CYP2C8 Inhibitors

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI with strong inhibitors of CYP2C8 is contraindicated.

Although not studied, use of UPTRAVI with moderate CYP2C8 inhibitors (eg, teriflunomide and deferasirox) can be expected to increase exposure to the active metabolite of selexipag. Consider a less frequent UPTRAVI dosing regimen, eg, once-daily, when initiating in patients on a moderate CYP2C8 inhibitor. Reduce UPTRAVI when initiating a moderate CYP2C8 inhibitor.

CYP2C8 Inducers

Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Recommended starting dose is 200 mcg twice daily. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

Patients With Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).

‡Treatment period defined as 7 days after last intake of UPTRAVI or placebo.

‡§Only adverse reactions occurring ≥3% on UPTRAVI compared to placebo and with a placebo-corrected difference of ≥3% in the triple-combination subgroup vs the overall population are shown here.

§&Verbar;Only adverse reactions occurring ≥3% on UPTRAVI compared to placebo and with a placebo-corrected difference of ≥3% in the FC II triple-combination subpopulation vs the overall population are shown here.

&Verbar;¶Only adverse reactions occurring ≥3% on UPTRAVI compared to placebo and with a placebo-corrected difference of ≥3% in the FC III triple-combination subpopulation vs the overall population are shown here.

DRUG INTERACTIONS

CYP2C8 Inhibitors

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI with strong inhibitors of CYP2C8 is contraindicated.

Although not studied, use of UPTRAVI with moderate CYP2C8 inhibitors (eg, teriflunomide and deferasirox) can be expected to increase exposure to the active metabolite of selexipag. Consider a less frequent UPTRAVI dosing regimen, eg, once-daily, when initiating in patients on a moderate CYP2C8 inhibitor. Reduce UPTRAVI when initiating a moderate CYP2C8 inhibitor.

CYP2C8 Inducers

Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped.

DOSAGE AND ADMINISTRATION

Recommended Dosage

Recommended starting dose is 200 mcg twice daily. Tolerability may be improved when taken with food. Increase by 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If dose is not tolerated, reduce to the previous tolerated dose.

Patients With Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose is 200 mcg once daily. Increase by 200 mcg once daily at weekly intervals, as tolerated. Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).